The serologically detectable serum substance, Ss, is a protein variant controlled by the Ss locus in the S region of the Murine H-2 complex. This protein is present in different quantities in the sera of all mice. Mice carrying the H-2Kk haplotype have a low level of the Ss protein in their sera whereas mice of all other inbred strains have a high level of the protein. Our interest in the Ss protein has been motivated by the following three considerations: First, the Ss locus is borne by the major histocompatibility complex of the mouse and the question must therefore be asked, what relationship, if any, it has to the other loci in the complex. Second, recent data suggest an involvement of the Ss protein in complement function. Third, the finding that genes linked to the HL-A system of man influence complement activity suggests that a homologue exists in the HL-A complex. Recent experiments in our own as well as three other laboratories strongly implicate that the human counterpart of the murine Ss protein is C4.